Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance

Bustamante-Marin, Ximena M.; Yin, Weining; Sears, Patrick R.; Werner, Michael; Brotslaw, Eva; Mitchell, Brian J.; Jania, Corey M.; Zeman, Kirby L.; Rogers, Troy D.; Herring, Laura E.; Réfabert, L.; Thomas, Lucie; Amselem, Serge; Escudier, Estelle; Legendre, M.; Grubb, Barbara R.; Knowles, Michael R.; Zariwala, Maimoona A.; Ostrowski, Lawrence E.

doi:10.1016/j.ajhg.2018.12.009

Cited by 85 publications

(76 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has high allelic and locus heterogeneity with mutations in over 40 genes known, so far, to lead to PCD (Table S1). [3][4][5] These genes encode proteins that are either essential for the multiciliogenesis pathway or are structural and assembly proteins (cytoplasmic dynein assembly factors) of the motor machinery of the ciliary axoneme. 6 In the current study, we have used targeted NGS for the genetic investigation of PCD in a cohort of Egyptian families where PCD is highly clinically suspected.…”

mentioning

confidence: 99%

Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia

et al. 2019

View full text Add to dashboard Cite

Primary ciliary dyskinesia (PCD) is a rare genetic disorder of motile cilia dysfunction generally inherited as an autosomal recessive disease. Genetic testing is increasingly considered an early step in the PCD diagnostic workflow. We used targeted panel next‐generation sequencing (NGS) for genetic screening of 33 Egyptian families with clinically highly suspected PCD. All variants prioritized were Sanger confirmed in the affected individuals and correctly segregated within the family. Targeted NGS yielded a high diagnostic output (70%) with biallelic mutations identified in known PCD genes. Mutations were identified in 13 genes overall, with CCDC40 and CCDC39 the most frequently mutated genes among Egyptian patients. Most identified mutations were predicted null effect variants (79%) and not reported before (85%). This study reveals that the genetic landscape of PCD among Egyptians is highly heterogeneous, indicating that a targeted NGS approach covering multiple genes will provide a superior diagnostic yield compared to Sanger sequencing for genetic diagnosis. The high diagnostic output achieved here highlights the potential of placing genetic testing early within the diagnostic workflow for PCD, in particular in developing countries where other diagnostic tests can be less available.

show abstract

mentioning

confidence: 99%

Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia

et al. 2019

View full text Add to dashboard Cite

show abstract

“…To characterize the effects of the genetic variant in CFAP57 on the function of motile cilia, we obtained human nasal epithelial (HNE) cells from the PCD subject and healthy controls. Cells were expanded in culture as conditionally reprogrammed cells (CRCs) (36), then allowed to differentiate using air-liquid interface cultures as previously described (22). Immunofluorescent staining of isolated ciliated cells from the control cultures showed CFAP57 reactivity along the entire length of the axoneme, while no positive staining was observed in cells from the PCD subject ( Fig.…”

Section: A Pathogenic Variant Of Cfap57 Causes Defective Ciliary Beatmentioning

confidence: 99%

“…Kit (Qiagen) and RT-PCR was performed using specific primers (Table S6) as previously described (22). For qRT-PCR, RNA was reverse-transcribed using an Applied Bioscience High-Capacity Reverse Transcription Kit (Thermo Fisher Scientific).…”

Section: Analysis Of Cfap57 Expression Rna Was Isolated From Cells Umentioning

confidence: 99%

“…HNE cultures (n=6) was measured as previously described (22,63). In hTEC cultures, CBF was measured in at least 5 fields obtained from each preparation.…”

Section: Ciliary Beat Frequency and Waveform Analysis The Ciliary Bementioning

confidence: 99%

“…In addition, mutations in two genes, CCNO (15) and MCIDAS (16), cause a PCD-like phenotype by greatly reducing the number of motile cilia. Although genetic variants that cause PCD have been identified in over 40 genes (2,(17)(18)(19)(20)(21)(22)(23), there are individuals with confirmed clinical features of PCD but normal axonemal structure as determined by transmission electron microscopy, for whom the genetic basis of their disease is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mutation ofCFAP57causes primary ciliary dyskinesia by disrupting the asymmetric targeting of a subset of ciliary inner dynein arms

Bustamante-Marin

Horani

Stoyanova

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

word count: 247 Text word count, without methods: 3856 Abstract (247/ 250 words)Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis, and is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious TEM structural phenotype for pathogenic variants using whole exome capture and next generation sequencing. The population sampling probability (PSAP) algorithm identified one subject with a homozygous nonsense variant [(c.1762C>T) p.(Arg588*) exon 11] in the uncharacterized CFAP57 gene. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Analysis of cells from the PCD patient shows a loss of CFAP57, reduced beat frequency, and an alteration in the ciliary waveform. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs)recapitulates these findings. Phylogenetic analysis showed that CFAP57 is conserved in organisms that assemble motile cilia, and CFAP57 is allelic with the BOP2 gene identified previously in Chlamydomonas. Two independent, insertional fap57Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass spectroscopy showed that CFAP57 is missing, and the "g" inner dyneins (DHC7 and DHC3) and the "d" inner dynein (DHC2) are reduced. Our data demonstrate that the FAP57 protein is required for the asymmetric assembly of inner dyneins on only a subset of the microtubule doublets, and this asymmetry is essential for the generation of an effective axonemal waveform. Together, our data identifies mutations in CFAP57 as a cause of PCD with a specific defect in the inner dynein arm assembly process. Significance (119/120 words)Motile cilia are found throughout eukaryotic organisms and performs essential functions.Primary ciliary dyskinesia (PCD) is a rare disease that affects the function of motile cilia.By applying a novel population sampling probability algorithm (PSAP) that uses large population sequencing databases and pathogenicity prediction algorithms, we identified a variant in an uncharacterized gene, CFAP57. This is the first reported example of PCD caused by a mutation that affects only a subset of the inner dynein arms, which are needed to generate the waveform. CFAP57 identifies an address for specific dynein arms. These findings demonstrate the effectiveness of the PSAP algorithm, expand our understanding of the positioning of dynein arms, and identify mutations in CFAP57 as a cause of PCD.

show abstract

Advances in the Diagnosis and Treatment of Primary Ciliary Dyskinesia

Dunsky

Menezes

Ferkol

2021

JAMA Otolaryngol Head Neck Surg

View full text Add to dashboard Cite

IMPORTANCE Primary ciliary dyskinesia (PCD) is a rare, inherited condition involving motile cilia that line the upper and lower respiratory tracts, leading to chronic infections of the paranasal sinuses, middle ear, and bronchi that begin during infancy. Unfortunately, despite its early presentation, PCD is often recognized late.OBSERVATIONS People with PCD have diverse clinical manifestations, including chronic upper and lower respiratory tract disease, laterality defects, and subfertility. Through efforts of multinational clinical collaboratives, 4 cardinal features have been described that identify people who likely have PCD: unexplained neonatal respiratory distress, left-right laterality defects, daily wet cough, and nonseasonal rhinosinusitis beginning before 6 months of age. Recent advances in the understanding of the genetics and pathogenesis of the disease have led to a revolution in the approach to screening and diagnostic testing. Moreover, PCD has a broad clinical spectrum, and genotype-phenotype associations are beginning to be recognized. CONCLUSIONS AND RELEVANCEA high index of suspicion remains critical in diagnosing PCD.Children who have at least 2 of the major clinical features should be considered for further evaluation. Nevertheless, while newer tools have improved diagnostic capabilities, there is no single test that will diagnose every person with the disease. In people suspected of having PCD, nasal nitric oxide measurement is a useful screen, followed by diagnostic genetic testing and if negative, ciliary ultrastructural analysis. Despite otolaryngologic manifestations being common in infancy and persisting into adulthood, they have been understudied. Indeed, there are few randomized clinical trials examining the medicosurgical approaches to respiratory disease.

show abstract

Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance

Cited by 85 publications

References 83 publications

Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia

Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia

Mutation ofCFAP57causes primary ciliary dyskinesia by disrupting the asymmetric targeting of a subset of ciliary inner dynein arms

Advances in the Diagnosis and Treatment of Primary Ciliary Dyskinesia

Contact Info

Product

Resources

About